Spontaneous growth hormone secretion increases during puberty in normal girls and boys.

0021-972X/91/7301-0428$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society

Vol. 73, No. 2 Printed in U.S.A.

Spontaneous Growth Hormone Secretion Increases during Puberty in Normal Girls and Boys* SUSAN R. ROSE, GIOVANNA MUNICCHI, KEVIN M. BARNES, GERDINE A. KAMP, M. MERCEDES URIARTE, JUDITH L. ROSS, FERNANDO CASSORLA, AND GORDON B. CUTLER, JR. Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (G.M. K.M.B., G.A.K., M.M.U., F.C., G.B.C.), Bethesda, Maryland 20892; the Pediatrics Department of the University of New Mexico Medical Center (S.S.R.), Albuquerque, New Mexico 87131; and the Department of Pediatrics, Medical College of Pennsylvania (J.L.R.), Philadelphia, Pennsylvania 19129

ABSTRACT. To test the hypothesis that GH secretion increases during puberty, we measured GH levels in samples obtained every 20 min for 24 h from 132 normal children and adolescents. In both girls and boys, GH levels increased during puberty. The increase in mean levels was earlier in girls than boys, was most evident at night, and was due to increased pulse amplitude rather than a change in pulse frequency. The mean nighttime GH level in girls with bone ages (BA) greater than 12 to 14 yr were significantly greater than the mean level in girls with BA less than 8 yr (7.3 ± 3.0 vs. 3.4 ± 1.7 Mg/L; P < 0.01) and were greatest at breast stage 3 (7.9 ± 2.5 ng/L). GH pulse amplitude increased significantly before pubertal onset in girls and was significantly greater at BA greater than 12 to 14 yr than at BA of 8 yr or less (13.9 ± 6.0 vs. 7.9 ± 4.8 Mg/L; P < 0.01) and greatest at breast stage 3 (15.0 ± 6.3 Mg/L). The pubertal increase in GH secretion was delayed in boys compared to girls, with the lowest mean 24-h GH and mean nighttime GH values in boys with BA greater than 8 to 11 yr. The mean nighttime GH level at BA greater than 11 to 13 yr in

A

DOLESCENT girls grow at their fastest rate early in puberty, whereas adolescent boys grow at their fastest rate near or after the middle of puberty (1, 2). Hypothetical mechanisms for the pubertal growth spurt include direct actions of sex steroids on epiphyseal cartilage and indirect actions of these hormones through stimulation of GH and insulin-like growth factor-I (IGF-I). To our knowledge, no prior study has included a sufficient number of normal adolescents to permit detailed Received June 11, 1990. Address all correspondence and requests for reprints to: Dr. Susan Rose, Department of Pediatrics, University of New Mexico Medical Center, Albuquerque, New Mexico 87131. * During part of this study, Dr. Rose received support from Eli Lilly Co. (Indianapolis, IN) and Serono Pharmaceuticals (Braintree, MA). The NIDDK and the National Hormone and Pituitary Program (University of Maryland School of Medicine) provided support for the National Hormone and Pituitary Program GH RIA.

boys was significantly greater than that in the boys with BA greater than 8 to 11 yr (5.8 ± 2.9 vs. 3.5 ±2.1 ^g/L; P < 0.05) and was greatest at a testicular volume of more than 10 to 15 mL (6.5 ± 2.0 fig/L). The mean nighttime GH pulse amplitude in boys was significantly greater at BA greater than 11 to 13 yr than at BA greater than 8 to 11 yr (13.9 ± 5.1 vs. 7.3 + 2.6 /*g/L, P < 0.05) and was greatest at a testicular volume greater than 20mL(15.8± 12.0 jig/L). The mean nighttime GH levels correlated inversely with body mass index in both sexes, although the correlation achieved statistical significance only for the girls, being stronger in breast stage 3 to 5 girls (r = -0.57 P = 0.0007; n = 32) than in stage 1 and 2 girls (r = -0.38; P = 0.03; n = 32). These observations in normal adolescents emphasize the importance of interpreting spontaneous GH levels in short children in relation to normative data appropriate for sex, body mass, and bone age or pubertal stage. (J Clin Endocrinol Metab 7 3 : 428-435, 1991)

description of the changes in GH secretion during adolescence. Thus, we sought to examine in greater detail the developmental and sex-specific patterns of GH secretion during puberty. We hypothesized that mean plasma GH levels increase as children progress through puberty, that the earlier pubertal growth spurt in girls would be associated with an earlier pubertal rise in GH secretion, and that differences in body mass among children of normal weight and height might influence spontaneous GH secretion. We evaluated 24-h GH profiles in 132 normal girls and boys representing all pubertal stages [46 previously reported (3, 4)].

Materials and Methods Subjects One hundred and thirty-two children (64 girls) between the ages of 4-18 yr were recruited through the Normal Volunteer

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GH SECRETION DURING NORMAL PUBERTY

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further subdivided into those younger than 8 yr and those 8 yr and older, and prepubertal boys were subdivided into those younger than 9 yr and those 9 yr and older (Table 1). These two methods of grouping the data were considered important in defining developmentally appropriate normal ranges, since short children with delayed puberty often have a discordance between their chronological age and bone age (BA) or pubertal stage (8, 12). When group assignment was changed from BA grouping to pubertal stage grouping, many of the children were shifted in their grouping (Table 2).

Office at the NIH. They were Caucasian with rare exceptions (1 Cambodian, 1 Chinese, and 6 Hispanic). Heights were between the 5th and the 95th percentile for age. Weight for height, expressed as body mass index [BMI; weight (kilograms)/height (square meters)] in SD units for chronological age, was normal in every child (range, —1.83 to 2.00 SD; Table 1) (5). They were all in good health and were taking no medications. Ages at pubertal onset and patterns of progression through puberty were normal. Procedures

Hormone assays

The study was approved by the institutional review board of the NICHHD. Children were admitted to the hospital 1 night before study to allow accommodation to the setting. Each child and a parent provided informed consent for the study procedures. Height was measured at 0800 h, and the mean of 10 measurements by Harpenden stadiometer (6) was expressed as the SD score for age (7). Breast stage in girls was determined by the method of Tanner (8). Testicular volume in boys was determined by Prader orchidometer (9,10). A radiograph of the left hand and wrist was used to evaluate bone maturation (11). Spontaneous GH secretion was then assessed. A short iv catheter (void volume, 0.3 mL) was kept patent with small amounts of heparin. Blood samples for assay of GH were drawn every 20 min for 24 h, beginning at 0900 h. A blood sample for IGF-I was drawn at 0900 h on 2 consecutive days, with the mean value used for analysis. Children were encouraged to maintain usual activity and eating patterns during the 24-h study. Five prepubertal children were studied only at night because of their small size. Their results are included only when nighttime results are presented separately. GH data were grouped in two ways for analysis: first, according to bone maturation (Greulich and Pyle) in order to permit comparison of GH data in girls and boys in relation to their physical development, and second, by breast stage in the girls and testicular volume in the boys. Prepubertal girls were then

Plasma IGF-I was measured by Endocrine Sciences (Tarzana, CA). Plasma GH was measured in duplicate by polyclonal RIA (detection limit, 0.5 ng/L) at Hazleton Biotechnologies (Vienna, VA) (13). All samples from one child were measured in the same assay. To permit comparison between this GH assay and others, quality control standards were run in this assay, the National Hormone Pituitary Program assay (NHPP), and the Hybritech assays (San Diego, CA). The results of low, medium, and high standards were 1.1 ± 0.1, 3.6 ± 0.4, and 16.9 ± 2.0 mcg/L in the Hazleton assay; 2.4 ± 0.2, 3.8 ± 0.1, and 13.7 ± 0.1 in the NHPP assay; and 2.1 ± 1.2, 1.3 ± 0.7, and 8.3 ± 0.9 in the Hybritech assay, respectively (mean ± SD). Intra- and interassay coefficients of variation for the GH assay were 9.1% and 18.7%, respectively, at a level of 1.2 3.7% and 16.6% at 5.1 fig/L, and 3.1% and 9% at 18.5 Statistical analysis The mean 24-h GH level was the average of all 73 measurements [mean daytime GH, 37 values (0900-2100 h); mean nighttime GH, 36 values (2120-0900 h)]. For purposes of calculation, undetectable values were treated as equal to the detection limit. A pulse was defined as an increase in GH that exceeded the preceding nadir by 3 times the intraassay coefficient of variation (at the nadir concentration) (3).

TABLE 1. Characteristics of 132 normal children grouped by development according to breast stage in girls and according to testicular volume in boys Pubertal stage Girls (breast stage) 1A° IB 2 3 4 5 Boys [stage, testicular vol (mL)] 1A° 15-20 >20 5

n

Age (yr)

BA (yr)

Ht (SD units for age)

BMI (SD units for age)

IGF-I (U/mL)

10 16 6 8 13 11

6.5 [1.0] 9.6 [1.2] 11.1 [0.2] 12.7 [1.0] 13.5 [1.0] 15.3 [1.2]

6.2 [1.0] 8.7 [1.5] 10.7 [0.5] 12.4 [0.9] 13.5 [1.1] 15.8 [1.0]

0.2 [1.0] -0.2 [0.8] 0.1 [1.2] 0 [0.9] 0.5 [1.0] -0.1 [0.8]

0 [0.7] -0.6 [0.5] -0.6 [0.1] -0.7 [0.4] -0.4 [0.4] 0 [0.6]

0.9 [0.3] 0.9 [0.4] 2.0 [0.9] 1.9 [0.4] 2.3 [0.6] 2.1 [0.4]

18 18 7 12 6 5

6.9 [1.1] 10.7 [1.1] 12.4 [1.2] 12.8 [0.9] 14.9 [1.6] 16.0 [1.5]

5.8 [1.6] 9.5 [1.7] 12.3 [1.0] 12.8 [1.2] 14.6 [1.5] 16.5 [0.5]

0.3 [0.9] -0.5 [0.9] 0.4 [1.0] 0.3 [0.8] 0.8 [0.5] 0.6 [0.8]

-0.2 [0.7] -0.5 [0.7] -0.3 [0.5] -0.4 [0.4] 0.7 [1.2] 0.2 [1.0]

0.7 [0.3] 1.1 [0.3] 1.5 [0.2] 2.1 [0.5] 2.2 [0.9] 2.0 [0.5]

Values are means, with the SD in brackets. For the girls, 1A denotes age less then 8 yr, and IB denotes age greater than 8 yr. For the boys, 1A indicates age less than 9 yr, and IB denotes age 9 yr or greater. 0


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TABLE 2. Analysis of pubertal stage by BA BA (yr) 15-20

4

3 2

4

1 4 1

5 2 2

1 2 2

1 2

4 4

1 2 4 1

1 5

2 3

2

1 6

1 1

1

1

BONE AGE (years)

1

3

>20

4

5

0

According to Tanner (8, 9). Number of children. c Mean of left and right testicular volumes (11).

6

The 95% confidence limits for the mean nighttime GH level of each BA group or pubertal stage were estimated after logarithmic transformation of the data to approximate a Gaussian distribution (14). To compare results among BA groups and among pubertal stages, data were evaluated by analysis of variance, followed when appropriate by comparisons between individual groups with Student's two-tailed t test using the Bonferroni adjustment. The relationship between the nighttime GH levels and BMI was analyzed by linear regression separately for girls or boys not in puberty or in early puberty (stages 1 and 2) us. later stages of puberty (stages 3, 4, and 5). Results are shown as the mean ± SD unless indicated.

Results Spontaneous GH secretion according to bone maturation Both mean 24-h GH level and mean nighttime GH level increased in girls with BA greater than 8 to 10 yr, but decreased in boys with BA greater than 8 to 13 yr, so that the difference in their mean nighttime GH level was significant (P < 0.05; Figs. 1 and 2). The rise in mean GH levels in girls achieved statistical significance at BA greater than 12 to 14 yr compared with values at BA 8 yr or less (P < 0.01). In boys this rise achieved statistical significance at BA greater than 11 to 13 yr compared with values at BA greater than 8-11 yr (P < 0.05). Mean nighttime GH levels were significantly higher than mean daytime levels in both sexes in all groups (P < 0.01; Fig. 2). GH pulse frequency did not change significantly with bone maturation (Fig. 3). Mean nighttime pulse frequencies of 3.0-4.5 pulses/12 h in each group were significantly greater than the mean daytime pulse frequencies of 2.0-2.8 pulses/12 h (P < 0.05). The baseline GH concentration (between pulses) was often below the assay detection limit (66 ± 21% of

FIG. 1. Mean 24-h GH concentrations in prepubertal and pubertal girls and boys according to BA. • ; • , Significantly greater than the values in girls at BA 8 yr or less (P < 0.01). *, Significantly greater than the values in boys at BA greater than 8 to 11 yr (P < 0.05). The brackets indicate the SEM.

NIGHT DAY GIRLS < 8 BOYS < 8

GIRLS OOBOYS • •GIRLS O— —-OBOYS

8-10 10-12 12-14 8-11 11-13 13-15 BONE AGE (Years)

FlG. 2. Mean daytime and nighttime GH concentrations in girls and boys according to BA. Each nighttime value is significantly greater than each daytime value in the same BA group (P < 0.05). **, Significantly greater than values in girls at BA 8 yr or less (P < 0.01). *, Significantly greater than values in boys at BA greater than 8 to 11 yr (P < 0.01). f, Significant compared with the paired BA group in boys (P < 0.05). The brackets indicate the SEM.

daytime values; 46 ± 38% of nighttime values). There was no significant variation in percentage of either daytime or nighttime values below the detection limit among girls or among boys by BA groups. Comparing girls and boys, the percentage of GH values below the detection limit was significantly lower in girls at BA greater than 12 to 14 yr (32 ± 14%) than in boys at BA or less than 8 yr (52 ± 15%) and greater than 15 yr (56 ± 9%; P < 0.05). The higher GH concentration with increasing bone maturation resulted from increased pulse amplitude rather than increased pulse frequency. The pulse amplitude of the girls at BA greater than 8 to 10 yr was significantly increased relative to that of the boys at BA greater than 8 to 11 yr (P < 0.05; Fig. 3). In all groups mean pulse amplitude was greater at night than during the day.



25

20

20

10

o

LU

-BOYS

40 h GIRLS

PULSE AMPLITUDE

E,

431

15

1

t

5

V

k

t

t

s

t

f m

i

QC

O 10 X I •7

o

GIRLS • •

QC

O

B0YS0---O _ PULSE FREQUENCY

X

40 - GIRLS

2

20

£

10

- BOYS

3

•

c/5

JU

LU CO

I t •• #

Z) CL

0 GIRLS < 8 BOYS < 8

8-10 8-11

10-12 12-14 >14 11-13 13-15 >15

Bone Age (years) FIG. 3. Mean nighttime GH pulse amplitude (top) and pulse frequency (bottom) in girls and boys according to BA. **, Significantly greater than the values in girls at BA 8 yr or greater (P < 0.01). • , Significantly greater than the value in boys at BA greater than 8 to 11 yr (P < 0.05). 7, Significantly greater than values in the first and second groups of boys (P < 0.05). t, Significantly greater than values in boys of the same paired BA group (P < 0.05). The brackets indicate the SEM.

Mean nighttime GH concentrations were spread over a wide range in each BA group in each sex (Fig. 4, top panels). Spontaneous GH secretion according to breast stage in girls and testicular volume in boys Earlier as well as the current data suggest that the mean nighttime GH level is as useful diagnostically as the mean 24-h level (3, 15, 16). Since analysis of nighttime data in this study yielded the same conclusion as analysis of 24-h data, the analysis of the data by breast stage (girls) and testicular volume (boys) is presented only for the nighttime levels (Fig. 4, bottom panels). Mean nighttime GH levels were significantly increased at breast stages 2, 3, and 4 in girls and at testicular stages 3 and 5 in boys relative to values in the younger prepubertal children (P < 0.05). Pulse frequency and percentage of GH values below

s

'

BONE AGE (Years)

t

t

t •

T

8

*

S

.5 u

1A

1B

2

3

4 5 1A 1B PUBERTAL STAGE

2

3

4

5

FIG. 4. The shaded bars represent the mean and 95% confidence limits of the mean nighttime GH concentration in normal children according to BA in the top panels (left, girls; right, boys) and according to pubertal stage in the bottom panels [by breast stage for girls (left) and testicular volume for boys (right)]. Each point represents the mean nighttime GH level in one child.

the detection limit did not change significantly with pubertal stage in either girls or boys. However, the percentage of GH values below the detection limit was significantly lower in stage 4 girls (29 ± 13 %) than in younger and older prepubertal boys (54 ± 16% and 53 ± 18%) or boys with testicular volumes of 5-10 mL (58 ± 10%), greater than 15-20 mL (56 ± 10%), and greater than 20 mL (55 ± 8%; P < 0.05). In girls, mean pulse amplitude was significantly increased at all stages compared with that in younger prepubertal girls (P < 0.05). In boys, mean pulse amplitude was significantly increased at testicular volumes greater than 10-15 mL and greater than 20 mL compared with that in younger prepubertal boys (P < 0.05). The effect of body mass on GH secretion was examined in these children of normal height and weight. When data from all pubertal stages were combined, the mean nighttime GH level correlated inversely with BMI for girls (r = -0.43; P = 0.0004), but not for boys (r = -0.12; P = 0.31). This correlation was stronger in pubertal stage


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432

3-5 girls (r = -0.57; P = 0.0007) than in stage 1 and 2 girls (r = -0.38; P = 0.03; Fig. 5). IGF-I concentrations IGF-I concentrations were comparable in boys and girls at each pubertal stage and rose significantly by stage 3 (P < 0.05) compared with those in younger prepubertal children (Table 1). These data have been provided to Endocrine Sciences for addition to their normal data base.

Discussion We studied GH concentrations in blood samples obtained every 20 min for 24 h in 132 normal children and adolescents and examined the effects of sex, body mass, pubertal stage, and bone maturation on GH parameters. GH levels increased during pubertal development in both sexes, with the highest levels at midpuberty (stages 3 and 4 in girls, 3 and 5 in boys). The increase began before the appearance of clinical signs of puberty in girls, consistent with the observation that the pubertal growth spurt in girls often begins before the appearance of breast budding (1, 2). With bone maturation beyond 8 yr, mean GH levels and pulse amplitude increased in girls, whereas a decrease in these was observed in boys until after a BA of 11 yr was reached. Prior studies have suggested elevated GH during pu-

berty. Early studies suggested higher GH concentrations in children than in adults (17,18). Subsequently, at least 11 studies have addressed the question of whether 24-h GH levels in normal children and adolescents change with progression through puberty (Table 3) (19-29). However, to our knowledge, the current study is the first to compare spontaneous GH secretion among all stages of puberty in both girls and boys. The observations in the majority of studies indicate higher GH concentrations in adolescents (often grouped from several pubertal stages) than in prepubertal children. Our results confirm this and, in addition, reveal sex differences in the timing of this increase. Specifically, our results indicate an earlier pubertal increase in GH secretion in girls than in boys, with a significant increase in GH peak amplitude before the earliest clinical signs of puberty. We observed that mean GH concentrations and pulse amplitude in normal boys at BA greater than 8 to 11 yr or testicular volume 5 to 10 mL remain near prepubertal levels. Thus, if the results for short boys at pubertal stage 2 were compared with levels averaged across several pubertal stages, they might inappropriately be considered deficient. Boys at these BAs or at pubertal stage 2 are common among those who present for evaluation of short stature. These data emphasize the importance of developing normative data that are appropriate for each sex, pubertal stage, and level of bone maturation. Sex steroids increase GH levels in diagnosed patient groups (15, 30-45). GH levels were increased in pubertal PUBERTAL STAGE 3 , 4 1 5

PUBERTAL STAGE 1 & 2

FIG. 5. Correlation between mean nighttime GH levels and BMI (SD units) in children grouped according to breast stage (1 and 2 on the left and 3, 4, and 5 on the right) for girls (top) and according to testicular volume (1 and 2 on the left and 3, 4, and 5 on the right) for boys (bottom). The solid lines are the regression lines, and the dashed lines indicate the 95% confidence limits for individual observations.

o o

BOYS

r = -0.21 p = 0.19

BOYS

10 8 6 4 3

- • •

2 1.5

-2

-1

1

2 - 2

-1

Body Mass Index (SD Units)


r = -0.36 p = 0.08


433

TABLE 3. Summary of published studies of mean spontaneous GH levels in normal adolescents, expressed as ti percentage of the level in

prepubertal children of the same sex GH: % of prepubertal value Stage of puberty

Ref. no. Prepubertal

3

2

Studies of males and females 19 20 28 Studies of females 21 22 24 27 Current study' Studies of males 21 22 23 24 25 26 29 Current studyc

5

756 (10). 144 (5) 121 (18)

(4)° (7) (15) (12) (4) (6) (5)

Young adult

4

58(1)

420 (8) 68 (6)

.106 (7). .113 (7). .133 (13). _106 (8)_

Younger/older 100(10) 148(16)161 (6)

(17) 95 (15) (7) [ (26) 138 (9) (18) [ (11) 70 (14) (7) 122 (5) (5) 84 (4) Younger/older 100 (18) 113 (18)116 (7)

70 (3) 71 (23)

]147(10)

248 (8)

58 (22)

242 (13)

113(11)

.295 (9). 82 (5) _250 (7). .148 (9)_ .206 (16). 152 (2) 105 (4) [ 66 (5) 213 (12)

116 96)

1 115 (13)

58(1)

123 (7) 48(13) 61 (19) 44 (16) 58(11)

164 (7)

" The number of subjects is given in parentheses. 6 Data grouped from several pubertal stages are indicated by brackets. 0 Data for the boys are grouped by testicular volume, for the girls by breast stage.

short children compared with levels in prepubertal short children (15, 30-32), in patients after exposure to exogenous sex steroids (33-38), and in children with untreated precocious puberty (39). In delayed puberty, decreased GH levels were described (29, 40, 41). The same has been observed in sex steroid-deficient older girls with Turner's syndrome (42). However, the difference between prepubertal and pubertal GH secretion was not always recognized when comparing short patients who were prepubertal to pubertal normal children (43, 44). Previous studies have shown decreased spontaneous and stimulated GH levels in obesity (45-48). However, to our knowledge a similar effect of body mass has not been shown previously in normal children. Our study found such a relationship among normal girls, particularly at pubertal stages 3-5, but not among boys. We hypothesize that the sex difference in the effect of body mass on GH levels may be related to the greater gain in body fat during puberty in girls. A similar inverse relationship between spontaneous GH levels and BMI has been observed in girls with precocious puberty (49). Interpretation of GH levels in individual patients must take into account the variation in GH values observed

among different GH assays (50). Since commercially available assays currently yield markedly different GH levels for the same sample, the normal levels reported here cannot be assumed to apply for GH assays other than the one used in this study. We conclude that spontaneous GH levels and GH pulse amplitudes increase significantly in older prepubertal girls and in pubertal girls and by stage 3 in boys, and are significantly elevated in girls at BA greater than 8 to 10 yr compared with those in boys at BA greater than 8 to 11 yr. Spontaneous GH levels correlate inversely with BMI in girls even for differences in BMI that are within the normal range. Thus, measurements of spontaneous GH levels in adolescents with growth failure should be interpreted in relation to normative data that are appropriate for sex, body mass, pubertal stage, and BA.

Acknowledgments We thank the children, their families, the nurses of the 9 West Ward of the NIH Clinical Center, and Barbara Filmore, without whom this study could not have been performed. We appreciate the technical


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assistance of Maral Kibarian, Lynnelle Thomas, LaJuan Montgomery, and Kathleen Kreider.

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Gonadotropin secretory dynamics during puberty in normal girls and boys.

Luteinizing Hormone Secretion during Gonadotropin-Releasing Hormone Stimulation Tests in Obese Girls with Central Precocious Puberty.

Serum prolactin, FSH and LH during puberty in girls and boys.

Growth hormone and puberty.

Supplemental growth hormone increases the tumor cytotoxic activity of natural killer cells in healthy adults with normal growth hormone secretion.

Acute clonidine administration potentiates spontaneous diurnal, but not nocturnal, growth hormone secretion in normal short children.

Effect of androgen on growth hormone secretion and growth in boys with short stature.

The effect of puberty on fat oxidation rates during exercise in overweight and normal-weight girls.

Corticosteroid-induced growth hormone secretion in normal and obese subjects.

Mean 24-hour growth hormone and testosterone concentrations in relation to pubertal growth spurt in boys with normal or delayed puberty.

Resumption of puberty in girls and boys following removal of the histrelin implant.

Is high-dose growth hormone treatment during puberty Worthwhile?

Growth hormone deficiency during puberty reduces adult bone mineral density.

Growth and sexual maturation in normal puberty.

Growth hormone deficiency throughout puberty.

Physiological growth hormone secretion in adult growth hormone deficiency: comparison with normal controls.

Melatonin secretion during adrenarche in normal human puberty and in pubertal disorders.

Changes in vertebral bone density in black girls and white girls during childhood and puberty.

Growth hormone receptor gene expression in puberty.

Growth hormone-binding protein activity is inversely related to 24-hour growth hormone release in normal boys.

Pulsatile growth hormone secretion in patients with acromegaly and normal men: the effects of growth hormone-releasing hormone infusion.

Influence of human corticotropin-releasing hormone and adrenocorticotropin upon spontaneous growth hormone secretion.

Pyridostigmine blocks the inhibitory effect of glucocorticoids on growth hormone-releasing hormone stimulated growth hormone secretion in normal man.

Comparison of Behavioral and Sexual Problems between Intellectually Disabled and Normal Adolescent Boys during Puberty in Yazd, Iran.